Novel tetralin derivatives

ABSTRACT

This invention relates to novel derivatives of tetralin, to the processes for their preparation, to their use as aminopeptidase inhibitors and to their end-use application as immunomodulators and as analgesic agents.

This invention relates to novel derivatives of tetralin, to theprocesses for their preparation, to their use as aminopeptidaseinhibitors and to their end-use application as immunomodulators and asanalgesic agents.

More specifically this invention relates to 3-aminonaphthalene-2-onederivatives of the formula ##STR1## the enantiomeric forms and mixturesthereof, and the pharmaceutically acceptable salts thereof wherein thedotted lines represent facultative double bonds, R₁ is H, F, Cl, C₁₋₆alkyl, OH, C₁₋₆ alkoxy, C₁₋₆ alkyl thio, C₁₋₆ acylamino, or C₁₋₆acyloxy, R₂ is H, Cl, F or C₁₋₆ alkyl, each of R₆, R₇, R₈ and R ₉ is H,Cl, F, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkoxy, aryl or aralkyl andwhen R₆ and R₇, and R₈, and R₈ and R₉ are taken together with the carbonatoms to which they are attached form a 5-6 membered carbocyclic moietywith the proviso that the number of so-formed carbocyclic moieties islimited to less than 3, and with the further proviso that when thedepicted ring moiety having the facultative double bonds is saturatedthen any 5-6 membered carbocylic moiety formed therewith is alsosaturated.

As used herein the term aryl includes phenyl which may be substitutedwith Cl, F, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino radicals butpreferably is phenyl, the term aralkyl includes benzyl or phenethyl thephenyl moieties of which may optionally be substituted with Cl, F, C₁₋₆alkyl, C₁₋₆ alkoxy or C₁₋₆ alkylamino moieties, preferably aralkyl beingbenzyl or phenethyl. The term C₁₋₆ alkyl thiol embraces those radicals--S--C₁₋₆ alkyl, the term C₁₋₆ acylamino embraces radicals of theformula --NHC(O)R wherein R is H or C₁₋₆ alkyl, and the term C₁₋₆acyloxy embraces radicals of the formula --OC(O)R wherein R is H or C₁₋₆alkyl. (The C(O) moiety represents a carbonyl function.) Included withinthe C₁₋₆ alkyl and other C₁₋₆ hydrocarboxy moieties are the straight andbranched chain moieties, preferably methyl and ethyl. In general whenthe R₆ and R₇, R₇ and R₈, or R₈ and R₉ moieties form an additional ring,it is preferred that phenanthrenone moieties be formed, particularly atthe R₆ and R₇ or at the R₈ and R₉ positions.

The term "pharmaceutically acceptable acid addition salts" is intendedto apply to any non-toxic organic or inorganic acid addition salt of thebase compounds represented by Formula I. Illustrative inorganic acidswhich form suitable salts include hydrochloric, hydrobromic, sulphuricand phosphoric acid and acid metal salts such as sodium monohydrogenorthophosphate and potassium hydrogen sulfate. Illustrative organicacids which form suitable salts include the mono, di- and tricarboxylicacids. Illustrative of such acids are, for example, acetic, glycolic,lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric,citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic,phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic and sulfonic acidssuch as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Eitherthe mono or the di-acid salts can be formed, and such salts can exist ineither a hydrated or a substantially anhydrous form. In general, theacid addition salts of these compounds are crystalline materials whichare soluble in water and various hydrophilic organic solvents, which incomparison to their free base forms, generally demonstrate highermelting points and an increased chemical stability.

Racemic mixtures of enantiomers may be resolved by standard procedureswell known in the art and include such practices as fractionaIcrystallization, chromatographic techniques and the use of chiralauxiliary reagents.

In general, the preparation of the compounds of this invention may beeffected by chemical processes analogously known in the art. Of course,the choice of the pathway for the obtention of any specific compounddepends on the number and type of substituents for the given compound,by the ready availability of the starting materials and such otherfactors well understood by the ordinarily skilled artisan.

In those instances wherein R₁, R₂, R₆, R₇, R₈ and R₉ moieties arehydrogen the compound is prepared from naphthalene wherein a Birch typereduction to its 1,4 -dihydronaphthalene analog (3), followed by anepoxidation reaction with m chloroperbenzoic acid in acetonitrile yields2,3-epoxy-1,2,3,4-tetrahydronaphthalene which, upon treatment withaqueous ammonia, yields trans-3-amino 1,2,3,4-tetrahydro-2 -naphthalenol(5). The amine is N-protected preferably with a t-butyloxycarbonyl (BOC)although other protecting groups may similarly be used, and theN-protected compound (6) is oxidized to its analogous ketone (7)according to standard procedures such as with pyridinium dichromate(PDC), or with Dess-Martin periodinane. The protecting group is removedby cleavage under acidic conditions or by hydrogenolysis using standardtechniques well known in the art, e.g. using HCl, HBr, H₂ SO₄ and thelike, or hydrogenation in the presence of a catalyst, or by acidhydrolysis is an inert atmosphere (argon or nitrogen) to produce thedesired 3-amino-3,4-dihydro-2(1H)-naphthalenone (8) (as a salt). Thisseries of reactions is depicted in Reaction Scheme A. ##STR2##

Optically active (+) and (-)-3-amino-3,4-dihydro 2(1H)-naphthalenonesare synthetized according to Scheme A wherein racemictrans-3-amino-1,2,3,4- tetrahydro-2-naphthalenol is resolved via theformation of diastereoisomeric phenylpropionyl amides. For example,racemic trans 3-amino 1,2,3,4,-tetrahydro-2-naphthalenol is coupled withR-(-)-2-phenyl-propionic acid to produce 2 diastereoisomeric amides (9)and (10) which are readily separated by chromatography on silica gelusing standard techniques. The chiral auxiliary group is then removed byhydrolytic cleavage in aqueous HCl and the resulting optically active3-amino-1,2,3,4-tetrahydro-2-naphthalenols are converted to theirBOC-amino derivatives, oxidized and deprotected as described for thegeneral reactions of Scheme A. The two diastereoisomeric amides are ofthe formulae ##STR3## wherein φ represents phenyl.

In those instances wherein the R₆ -R₉ substituents are other thanhydrogen, alternate routes of synthesis are required using intermediateswhich are suitable for a variety of synthetic pathways. It is convenientto utilize the appropriately R₆, R₇, R₈, R₉ substituted benzaldehydes asstarting materials for conversion to the desired intermediates (i.e.,N-protected-α,α-diethoxymethyl-β-aminopropanol derivatives (16) of theR₆ -R₉ substituted benzaldehydes). In this synthetic approach, the R₆-R₉ benzaldehydes are generally commercially available compounds, but inthose instances wherein any particular benzaldehyde or naphthalenealdehyde is not available it may be prepared by techniques analogouslyknown in the art. The preparation of the intermediates is summarized bythe depiction of the following scheme. ##STR4## wherein the wavy linesof the compounds of Formulae 14 to 16 designate that these groups can bein either the R or the S configurations, "R₆₋₉ " is a short-handcomposite of the R₆, R₇, R₈ and R₉ substitutents (representing mono-,multi-, or non-substituted intermediates as the R₆, R₇, R₈ and R₉substituents are shown and defined for Formula I), Pg represents anitrogen protecting group and Et represents ethyl.

The foregoing scheme involves the conversion of the aldehyde (11) to itsnitroethenyl derivative (12) by treatment with nitromethane, in thepresence of ammonium acetate. The reaction takes place in acetic acidunder reflux conditions for about 2-6 hours. The nitroethenyl moiety isreduced, preferably with sodium borohydride (although other reducingagents may similarly be used) and the so reduced compounds (13) arereacted with a monodialkylacetal of glyoxal (preferablymonodiethylacetal of glyoxal) using a basic catalyst (preferablypotassium carbonate) at about 50° C. in an inert atmosphere (argon ornitrogen) for about 1 to 4 hours to yield a compound (14) bearing anα,α,-diethoxymethyl-β-nitropropanol moiety. The resulting intermediatesare chemically reduced, preferably in a closed system under atmosphericpressure or under pressure (50-70 psi) by reaction with hydrogen in thepresence of Raney nickel using isopropanol as solvent. The resultingamino moiety is protected with a suitable protecting group, preferablyusing di-t-butyl-dicarbonate or benzylchloroformate (producing BOC orCBZ protecting groups respectively). In each of the foregoing stepsstandard procedures and methodology well known to the person of ordinaryskill in the art are utilized. At this juncture in the synthesis towardthe obtention of the desired compounds of Formula I, it is convenient toseparate diastereomeric pairs of enantiomers. In general such separationmay be effected by standard techniques well known in the art. Forexample using chromatographic techniques, sequential elution from silicagel with varying concentrations of solvent mixtures, and fractionalcrystallization will afford separation of the diastereomeric forms.

The preparation of compounds of Formula 20, wherein R₁ and R₂ arehydrogen, may conveniently be effected by the procedure depicted in thefollowing reaction scheme. ##STR5##

The foregoing Reaction Scheme C involves the treatment of theN-protected amino hydroxy acetals (16) with strong acids, the choice ofacid depending on the route of synthesis desired and/or whether or notthe R₆₋₉ substituents are electron donating. For example, treatment ofcompounds 16 with 37% HCl at temperatures of about 80°-100° C. for 2 to10 minutes produces 3-amino-1,2,3,4-tetrahydro-1,2-naphthalenediols (18)via an internal Friedel-Crafts type alkylation of the amino hydroxyaldehydes of Formula 17 or the3-amino-1-chloro-1,2,3,4-tetrahydronaphthalenol intermediates (19),formed via an S_(N) 1-type reaction of chloride ions, which are warmedunder acidic conditions to effect a Pinacol rearrangement to producecompounds 20. Alternatively, compounds 20 may be produced directly byrefluxing the N protected hydroxy acetals (16) with trifluoro aceticacid for about 2-5 hours. Still another method for producing thecompounds 20 is by treating those intermediates of Formula 16 bearingelectron donating groups (e.g., alkoxy and alkylamino) with hydrochloricacid for about 2-10 minutes at about 80°-100° C.

In those instances wherein it is desired to prepare final compoundswherein R₁ and R₂ are hydrogen and the Pinacol rearrangement is notpreferred, compounds (18) and (19) may be chemically reduced usingstandard hydrogenation procedures such as by treatment with hydrogen inthe presence of a catalyst. The resulting 2-hydroxy-3-amino compoundsare N-protected, oxidized and deprotected as describe above.

The compounds (18) and (19) are also useful intermediates to introduce afunctional group at the 1-position and thus have access to compounds ofFormula I wherein R₁ is H and R₂ is fluoro, chloro, alkyl, alkoxy oralkylamino, or wherein R₁ and R₂ are both halogen. This set of reactionsis illustrated by Reaction Scheme D. ##STR6##

Reaction Scheme D is initiated by an intramolecular chloroalkylationreaction by treating compounds (16) with 37% aqueous HCl at 80°-100° C.for 2 to 5 minutes (typically 3 minutes) to form3-amino-1-chloro-1,2,3,4 -tetrahydro-2-naphthalenol derivatives (21).Since the starting material, compounds (16) has two chiral centers, itconsists of two pairs of enantiomers which are diastereoisomeric thatare resolved using standard techniques. Starting from the suitableenantiomers pair, the foregoing process results in the production ofcis-chlorohydrin (i.e., the chloro substituent and the hydroxyl functionare in a cis- relationship). Following the intramolecularchloroalkylation reaction the amino function is protected with an acidlabile protecting group (preferably with a BOC protecting group). TheN-protected cischlorohydrin is subjected to a replacement reaction usinga fluoride ion source reactant. For the conversion of cischlorohydrin tothe corresponding trans-fluorohydrin it is preferred to utilize apolymeric ion resin (e.g., Amberlyst A-26F) wherein the reactants arerefluxed in an appropriate solvent. Of course, other fluoro ion-sourcemay similarly be used [e.g., tetrabutylammonium fluoride (Bu₄ NF),cesium fluoride or potassium fluoride]. Following fluorination theresulting trans-fluorohydrins (22) are oxidized to the fluoroketones anddeprotected in acid media to form the 1-fluoro-3 -amino3,4-dihydro-2(1H)-naphthalenones of Formula 23.

An alternate procedure to the obtention of1-fluoro-3-amino-3,4-dihydro-2(1H)-naphthalenones is illustrated in thefollowing scheme: ##STR7##

The alternate procedure for the preparation of the 1-fluoro compounds ofFormula 18 is initiated by N-protecting the trans-chlorohydrins (24),(formed by reaction of the suitable enantiomers pair of compounds (16)with HCl) followed by treatment of the N-protected trans-chlorohydrinswith a base, preferably with 1,8-diazobicyclo[5.4.0] undec-7-ene (DBU) asuitable solvent (tetrahydrofuran) under reflux followed by treatment ofthe resulting 2,3-epoxides (25) with 70% HF/pyridine (diluted in anappropriate solvent, e.g., diethyl ether) to produce fluorohydrins (26)which are oxidized and N-deprotected (as previously described) toproduce the desired 1-fluoro-3-amino-R₆₋₉ -substituted3,4-dihydro-2(1H)-naphthalenones (23).

Similarly, reaction of the N-protected cis-chlorohydrins of Formula 21with the appropriate primary amine (i.e., RNH₂ wherein R is alkyl) in anaprotic solvent (e.g., tetrahydrofuran) yields the1-alkylamino-3-N-protected amine 1,2,3,4-tetrahydro-2-naphthalenolswhich, following the N-protection of the 1-position alkylamino,oxidation and deprotection steps, yields the desired3-amino-1-aminoalkyl-3,4-dihydro-2(1H)naphthalenones.

To prepare compounds wherein R₁ is H and R₂ is alkoxy, the epoxides ofFormula 25 are treated with an alcohol in the presence of a Lewis acid(e.g., titanium (IV) isopropoxide) to produce 1-alkoxy analogs ofcompounds 26 and these are oxidized and N-deprotected to produce thedesired 1-alkoxy 3-amino-3,4-dihydro-2(1H)naphthalenones of Formula I.Similarly, to produce compounds of Formula I wherein R₁ is H and R₂ isalkyl, the epoxides of Formula 25 are reacted with an appropriateorganometallic reactant (e.g., a Grignard reagent, cuprate,organolithiums, organoalanes, organo zincs) according to standardtechniques to produce the 1-alkyl-3-amino 3,4-dihydro-2-naphthalenonesof Formula I.

In those instances wherein it is desired to prepare compounds of FormulaI wherein R₁ and R₂ are both fluoro, cischlorohydrins (21) are acylatedto form corresponding benzoylamides (using benzoyl chloride) and theseamides are treated with thionyl chloride to form an oxazole, (i.e., acompound of Formula 27 ##STR8## wherein φ represents phenyl), which issequentially treated with lithium hydroxide in a methoxyethanol/watermixture and the resulting alcohol is oxidized to its corresponding1-keto analog. The ketone is treated with diethylaminosulfur trifluoride(DAST) to yield the corresponding 1,1-difluoro analogs of compounds ofFormula 27. Treatment with aqueous acid hydrolizes off the oxazolemoiety to produce the desired 1,1-difluoro-1,2,3,4tetrahydro-2-naphthalenols which are N-protected, oxidized andN-deprotected to their corresponding ketones of Formula I. All of theseforegoing reactions use procedures analogously known in the prior art.

In those instances wherein it is desired to prepare compounds not havingany aromatic ring system nor having any reducible functions, it isgenerally preferred to reduce any aromatic ring prior to oxidation ofthe 2-hydroxy function to its ketone. Preferably the compounds arehydrogenated under pressure (60 to 70 psi) in acetic acid over platiniumoxide at room temperature. The resulting compounds are converted tocompounds of Formula I according to the foregoing chemistry. ##STR9##

The preparation of compounds wherein R₁ is a thiol may be accomplishedby reacting a 2,3-epoxide intermediate with a sodium thiolate intetrahydrofuran according to standard reaction conditions. Similarly,using standard acylation procedures, such as reaction of a 1-OHintermediate with an acid chloride or anhydride, the 1-position acyloxyanalogs may be formed, and by reacting a 1-position amine with an acidchloride or anhydride using standard Procedures will effectacylamination. Following such reactions the compounds may be convertedto the desired final products of Formula I by using the techniquesherein described and exemplified.

In general the foregoing reactions all use processes and techniquesanalogously described in the art. These processes, as adopted for theparticular compounds of this invention, are described by the followingspecific examples.

EXAMPLE 1 3-Amino-3,4-dihydro-2-(1H)-naphthalenone, hydrochloride

Step A:

2,3-Epoxy-1,2,3,4-tetrahydronaphthalene

A solution of metachloroperbenzoic acid (55%, 22.8 g) in acetonitrile(190 ml) was added dropwise over 15 min to a solution of1,4-dihydro-naphthalene (7.86 g) in acetonitrile (100 ml) at 0° C. Theresulting mixture was stirred for 6 hours at room temperature. Themixture was concentrated to about 50 ml under reduced pressure, dilutedwith methylene chloride and filtered. The filtrate was washed with 10%aqueous sodium sulfite, saturated aqueous sodium hydrogenocarbonate,saturated aqueous sodium chloride, dried over magnesium sulfate andconcentrated in vacuo. The resulting solid (8.45 g) was chromatographed(silica gel, 150 g, elution with ethyl acetate:hexane, 1:9) to give thetitle compound as a solid (5.81 g).

Step B:

Trans-3-tert-butoxycarbonylamino-1,2,3,4 tetrahydro 2-naphthalenol

A suspension of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene (5.66 g) in 25%aqueous ammonia (100 ml) was warmed in a bomb at 100° C. for a period of4 hours. The mixture was evaporated under reduced pressure and theresidue was treated with a solution of di tert-butyl dicarbonate (8.18g) in methanol (100 ml). After stirring overnight the mixture wasconcentrated in vacuo. Recrystallization of the residue from achloroform/ hexane mixture yielded 6.12 g of the title compound as awhite solid, m.p. 149°-150° C.

Step C:

3 Tert-butoxycarbonylamino-3,4-dihydro-2(1H)-naphthalenone

Under argon to a solution of trans-3tert-butoxycarbonylamino-1,2,3,4-tetrahydro-2-naphthalenol (2.02 g) inmethylene chloride (40 ml) was added pyridinium dichromate (4.3 g),molecular sieves 3A (6.3 g) and acetic acid (0.76 ml). After 1 hourstirring at room temperature the mixture was poured on a silica gelcolumn (120 g, elution with ethyl acetate: cyclohexane, 1:3) to afford acrude material which was recrystallized from a diethyl ether/cyclohexanemixture to give the title compound (634 mg) as a white solid, m.p.104°-105° C.

Step D:

3-Amino-3,4-dihydro-2-(1H)-naphthalenone, hydrochloride

Under argon 3-tert butoxycarbonylamino-3,4-dihydro-2(1H) naphthalenone(623 mg) was dissolved in diethyl ether (20 ml). A saturated solution ofhydrochloric acid in diethyl ether (16.5 ml) was then added. Stirring atroom temperature was maintained for 1 hour. The precipitate was filteredand dried in vacuo to yield the title compound (408 mg) as a whitesolid, m.p. 163° C. (dec.).

PREPARATION OF PURE ENANTIOMERS OF

3-Amino-3,4-dihydro-2(1H)-naphthalenone, hydrochloride

EXAMPLE 2 (+)-3-Amino-3,4-dihydro-2(1H)-naphthalenone, hydrochloride

Step A:

Trans-N-[(2R)-2-phenylpropanoyl]-3-amino-1,2,3,4-tetrahydro-2-naphthalenol,diastereoisomer A and diastereoisomer B

Under argon to a solution of R-(-)-2-phenylpropionic acid (505 mg) inmethylene chloride (10 ml) at 0° C. was added hydroxybenzotriazole,hydrate (530 mg) and dicyclohexylcarbodiimide (718 mg). The mixture wasstirred at 0° C. for 10 minutes before addition of racemic trans-3-amino1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride (723 mg) andN-methylmorpholin (438 mg) in methylene chloride (5 ml). Stirring wasmaintained at 0° C. for 3 hours and at room temperature overnight. Thereaction mixture was diluted with ethyl acetate and filtered.Evaporation of solvent gave the crude mixture of diastereoisomer A anddiastereoisomer B. The diastereoisomer separation was achieved bychromatography on silica gel [160 g, elution with ethyl acetate:cyclohexane, 1:9 (700 ml). 2:8 (1 1). 3:7 (1 1) 2:3 (1 1) and 1:1 (11)]. Diastereoisomer A obtained as a white solid (232 mg) wasrecrystallized in ethyl acetate/cyclohexane, m.p. 158° C., Rf=0.30(silica gel, ethyl acetate:cyclohexane. 1:1). Diastereoisomer B wasrecovered as a white solid (250 mg) and recrystallized in ethyl acetate,m.p. 179°-180° C., Rf=0.40 (silica gel, ethyl acetate:cyclohexane, 1:1).

Step B:

(+)-Trans-3-amino-1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride

Trans-N-[(2R)-2-phenylpropanoyl-3-amino-1,2,3,4-tetrahydro-2-naphthalenol,diastereoisomer A (183 mg) was refluxed in 6N aqueous hydrochloric acid(20 ml) for 4 hours. The reaction mixture was evaporated in vacuo andthe residue taken up in water. The aqueous solution was washed withethyl acetate and evaporated to give a white solid which wasrecrystallized from a methanol/ethyl acetate mixture to yield the titlecompound (99 mg).

Step C:(+)-Trans-3-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-2-naphthalenol

To (+)-trans-3-amino-1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride(94 mg) was added a solution of di-tert butyldicarbonate (110 mg) inmethanol (1.5 ml) and a solution of triethylamine (59 mg) in methanol(1.5 ml). The reaction mixture was stirred for 1 hour at roomtemperature and evaporated in vacuo. The residue was taken up inmethylene chloride, washed with water and saturated aqueous sodiumchloride and dried over magnesium sulfate. Evaporation of solvent gave acrude material which was crystallized from a cyclohexane/ethyl acetatemixture to yield the title compound as a white solid (74 mg), m.p.168°-169° C.

Step D:

(+)-3-Tert-butoxycarbonylamino-3,4-dihydro-2(1H)-naphthalenone

Under argon to (+)-trans-3-tertbutoxycarbonylamino-1,2,3,4-tetrahydro-2-naphthalenol (70 mg) inmethylene chloride (1 ml) was added Dess-Martin periodinane (172 mg).The mixture was stirred for 1 hour at room temperature under argon andfiltered through a silica gel column [10 g, elution with ethyl acetate:cyclohexane mixtures. 1:9 (150 ml) and 2:8 (50 ml)]. Evaporation ofsolvent gave a solid which was recrystallized from pentane to yield thetitle compound as white needles, m.p. 76° C.

Step E:

(+)-3-Amino-3,4-dihydro-2(1H)-naphthalenone, hydrochloride

The BOC protecting group of(+)-3-tert-butoxycarbonylamino-3,4-dihydro-2(2H)-naphthalenone (27 mg)was cleaved according to the procedure described in Example 1 step D toyield the title compound as a white amorphous solid (15 mg).

EXAMPLE 3 2-Amino-1,2-dihydro-3(4H)-phenanthrenone, trifluoroacetate2-Amino-1,2-dihydro-3(4H)-phenanthrenone, hydrochloride

Step A:

2-(2-Nitroethenyl)naphthalene

A mixture of 2-naphthaldehyde (12 g), nitromethane (13.8 g) and ammoniumacetate (5 g) in acetic acid (50 ml) was refluxed for 21/2hours. Thebrown mixture was poured into ice-water (100 ml) from which a yellowsolid separated. Filtration and drying in vacuo afforded the titlecompound (14.4 g).

Step B:

2-(2-Nitroethyl)naphthalene

To a suspension of sodium borohydride (4 g) in a mixture of dioxane (85ml) and ethanol (30 ml) was added dropwise a solution of2-(2-nitroethenyl)naphthalene (100 g) in dioxane (90 ml) over 30minutes. The flask was cooled with a cold water bath during addition.Stirring was maintained for an additional 11/2hours. Ice (100 ml) and50% aqueous acetic acid room temperature, concentrated in vacuo andextracted with methylene chloride. The organic layer was washed withwater, saturated aqueous sodium chloride and dried over magnesiumsulfate. The solvent was evaporated in vacuo to yield an oil which wascrystallized from acetic acid to give the title compound (6.79 g) as ayellow solid, m.p. 59°-60° C.

Step C:

α, α-Diethoxymethyl-β-nitro-2 naphthalenepropanol

A mixture of 2-(2-nitroethyl)naphthalene (6.79 g), glyoxalmonodiethylacetal (2.23 g) and potassium carbonate (0.26 g) was stirredat 50° C. under argon for 2 hours. The mixture was diluted with diethylether (50 ml) and water (50 ml) was added. The aqueous layer wasextracted with diethyl ether (3×20 ml) and the combined organicsolutions were washed with saturated aqueous sodium chloride (50 ml) anddried over magnesium sulfate. Evaporation of solvent yielded a residuewhich was chromatographed [silica gel 300 g, elution withcyclohexane:ethyl acetate, 9:1 (2 1) and with cyclohexane:ethyl acetate,8:2 (2 1)] to give the title compound (4.72 g) as a brown oil.

Step D:

α, α-Diethoxy-β-tert-butoxycarbonylamino-2-naphthalenepropanol

A mixture of α,α-diethoxymethyl-β-nitro-2-naphthalenepropanol (4.7 g)and Raney nickel in isopropanol (80 ml) was stirred under hydrogen atatmospheric pressure. When absorption of hydrogen was complete themixture was degased in vacuo for 15 minutes and filtered through celite.Evaporation of the solvent in vacuo yielded α,α-diethoxymethyl-β-amino-2-naphthalenepropanol (3.69 g) as an oil.

A solution of α,α-diethoxymethyl-β-amino-2-naphthalenepropanol (3.62 g)in methanol (15 ml) was treated with ditert-butyl-dicarbonate (2.68 g).The mixture was stirred for 11/2hours at room temperature, evaporatedand the residue was chromatographed [silica gel 300 g, elution withcyclohexane:ethyl acetate, 9:1 (1.5 1), 2:8 (2 1) and 7:3 (1 1)]. Twoisomers of the title compound were isolated, isomer A (1.57 g) as ayellow oil and isomer B (0.68 g) which could be crystallized frompentane to give the title compound as a white solid, m.p. 87° C. Rfisomer A=0.39, Rf isomer B=0.27 (silica gel, cyclohexane:ethyl acetate,4:1).

Step E:

(±)-(2Rm3S,4R)-2-Amino-4-chloro-1,2,3,4-tetrahydro-3-phenanthrenol,hydrochloride

α, α-Diethoxy-β-tert-butoxyoarbonylaminonaphthalenepropanol isomer A(239 mg) was stirred in 37% aqueous hydrochloric acid (10 ml) at 0° C.for 45 minutes and at 100° C. for 3 minutes. The flask was cooled withan ice water bath and the precipitate was filtered, washed with waterand dried in vacuo to give the title compound (113 mg) as a white solid.

Step F:

(±) -(2R, 3R, 4R)-2-Amino-4-chloro-1,2,3,4-tetrahydro-3-phenanthrenol,hydrochloride

α, α-Diethoxy-β-tert-butoxycarbonylaminonaphthalenepropanol isomer B(208 mg) was stirred in 37% aqueous hydrochloric acid (10 ml) at 0° C.for 2 hours and at 100° C. for 3 minutes. The flask was cooled with anice-water bath and the precipitate was filtered, washed with water anddried in vacuo to give the title compound (80 mg) as a white solid.

Step G:

(±)-2-Amino-1,2-dihydro-3(4H)-phenanthrenone, trifluoroacetate

2-Amino-4-chloro-1,2,3,4-tetrahydro-3-phenanthrenol, hydrochloride (40mg) was refluxed in trifluoroacetic acid (17 ml) for 31/2hours. Thesolvent was removed in vacuo and the residue was crystallized from acyclohexane/ethyl acetate mixture to yield the title compound (17 mg) asa cream colored powder.

Step H:

(±)-2-Amino-1,2-dihydro-3(4H)-phenanthrenone, hydrochloride

2-Amino-4-chloro-l,2,3,4-tetrahydro-3-phenanthrenol, hydrochloride (265mg) was refluxed in trifluoroacetic acid (25 ml) for 3 hours. The greenmixture was evaporated in vacuo, taken up into methanol and treated withactivated charcoal for 2 hours at room temperature. Filtration andevaporation yielded a yellow oil which was diluted with methanol andacidified with a solution of hydrochloric acid in diethyl ether. Themixture was evaporated and the acidification process was repeated.Evaporation gave a residue which was recrystallized in amethanol/diethyl ether mixture to afford the title compound (122 mg) asa cream colored powder.

EXAMPLE 4

2-Amino-1,2-dihydro-3-(4H)-phenanthrenone, hydrochloride (alternativesynthetic route)

Step A:

Trans-2-amino-1,2,3,4-tetrahydro-3-phenanthrenol, hydrochloride

A solution of(±)-(2R,3S,4R)-2-amino-4-chloro-1,2,3,4-tetrahydro-3-phenanthrenolhydrochloride (396 mg) in methanol (50 ml) was hydrogenated over 10%palladium on charcoal (109 mg) under atmospheric pressure at roomtemperature. When the theoretical amount of hydrogen was absorbed, thecatalyst was filtered and the solvent evaporated under vacuum to givethe title compound as a solid (315 mg).

Step B:

Trans-2-terbutoxycarbonylamino-1,2,3,4-tetrahydro-3-phenanthrenol

To a suspension of trans-2-amino 1,2,3,4-tetrahydro-3-phenanthrenolhydrochloride (315 mg) and diterbutyl dicarbonate (308 mg) in methanol(5 ml) was added dropwise a solution of triethylamine (153 mg) inmethanol (5 ml). The resulting mixture was stirred for 11/2hours at roomtemperature and concentrated under vacuum. Water was added to theresidue and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium chloride and dried overmagnesium sulfate Evaporation of solvents yielded the crude titlecompound (0.42 g) which was purified by chromatography on silica gel[100 g, elution with ethyl acetate:cyclohexane, 1:9 (0.5 1), 1:4 (1 1)and 3:7 (0.7 1)]. Evaporation of solvents yielded the title compound asa yellow solid (245 mg). Recrystallization in an ethyl acetate/cyclohexane mixture yielded pure trans2-terbutoxycarbonyl-amino-1,2,3,4-tetrahydro-3-phenanthrenol as a whitesolid (183 mg).

Step C 2-tertbutoxycarbonylamino-1,2-dihydro-3-(4H)-phenanthrenone

Under argon to a solution of trans2-tertbutoxycarbonylamino-1,2,3,4-tetrahydro-3-phenanthrenol (140 mg) inanhydrous methylene chloride (5 ml) was added Dess-Martin periodinane(281 mg). Agitation was maintained for 1 hour at room temperature andthe reaction mixture was filtered on silica gel (30 g, elution withethyl acetate:cyclohexane, 1:9). Evaporation of solvents gave the crudetitle compound (136 mg) which was recrystallized from a pentane/ethylacetate mixture. The title compound was obtained as white needles (89mg).

Step D:

2-amino-1,2-dihydro-3(4H)-phenanthrenone, hydrochloride

Under argon to a solution of2-tertbutoxycarbonylamino-1,2-dihydro-3(4H)-phenanthrenone (74 mg) inanhydrous diethyl ether (5 ml) was added a saturated solution ofhydrochloric acid in diethyl ether (5 ml). The mixture was stirred for 6hours and the formed precipitate was filtered and dried under vacuum toafford the title compound as a white solid (42 mg)

EXAMPLE 5 3-Amino-3,4-dihydro-2(1H)-phenanthrenone, hydrochloride

Step A:

1-(2-Nitroethenyl)naphthalene

1-Naphthaldehyde (20 g) was treated according to the procedure inExample 3 step A. The crude compound was recrystallized from acetic acidto yield the title compound (16.1g) as a yellow solid.

Step B:

1-(2-Nitroethyl)naphthalene

1-(2-Nitroethenyl)naphthalene (16.1 g) was reduced to the title compoundaccording to the procedure described in Example 3 Step B. The crudeproduct was crystallized from a methylene chloride/cyclohexane mixtureto give the title compound (6.27 g) as a yellow solid. Thecrystallization residue was chromatographed (silica gel, elution withcyclohexane:ethyl acetate, 95:5) and the purified product wasrecrystallized from pentane/diethyl ether to yield the title compound(6.1 g) as white needles, m.p. 45°-46° C.

Step C:

α, α-Diethoxymethyl-α-nitro-1-naphthalenepropanol

A mixture of 1-(2-nitroethyl)naphthalene (12.2 g), glyoxalmonodiethylacetal (3.98 g) and potassium carbonate (0.42 g) was stirredunder argon at 50° C. for 13/4hours. The mixture was diluted withdiethyl ether (100 ml) and water (100 ml) was added The aqueous layerwas re-extracted with diethyl ether (3×30 ml) and the combined organicsolutions washed with saturated aqueous sodium chloride (100 ml) anddried over magnesium sulfate Evaporation of solvent in vacuo gave aresidue which was chromatographed [silica gel, 330 g, elution with ethylacetate:cyclohexane, 1:9 (3 1) and 2:8 (2 5 1)]. After evaporation ofsolvents the title compound (7.76 g) was obtained as a yellow oil.

Step D:

α, α-Diethoxymethyl-α-tert-butoxycarbonylamino-1-naphthalenepropanol

A mixture of α, α-diethoxymethyl-β-nitro-1-naphthalenepropanol (7.75 g)and Raney nickel (0.8 g) in isopropanol (100 ml) was stirred underhydrogen at atmospheric pressure until hydrogen absorption stopped. Themixture was then degased for 15 minutes in vacuo and filtered throughcelite. The filtrate was evaporated in vacuo to yield α,α-diethoxymethyl-β-amino-1-naphthalenepropanol (6.37 g) as an oil.

A solution of α, α-diethoxymethyl-β-amino-1-naphthalenepropanol (6.37g), di-tert-butyl dicarbonate (4.73 g) in methanol (120 ml) was stirredat room temperature for 13/4 hours. The mixture was concentrated underreduced pressure and the residue was chromatographed [silica gel 280 g,elution with ethyl acetate:cyclohexane, 1:9 (1 1) and 2:8 (3 1)]. Twoisomers of the title compound were isolated as oils, isomer A (3.15 g)and isomer B (2.81 g). Rf isomer A=0.52, Rf isomer B=0.45 (silica gel,ethyl acetate:cyclohexane, 1:1). These oils could be crystallized frompentane, m.p. isomer A 93° C., isomer B 102° C.

Step E:

(±)-(1S, 2R, 3S)-3-Amino-1-chloro-1,2,3,4-tetrahydro-2-phenanthrenol,hydrochloride

A suspension of α,α-diethoxymethyl-β-tert-butoxycarbonylamino-1-naphthalenepropanol (250mg), isomer A was stirred in 37% aqueous hydrochloric acid at 0° C. for1 hour. The resulting emulsion was then stirred at 100° C. for 3 minutesand the flask was immediately cooled in an ice-water bath. Theprecipitate was filtered, washed with water and dried in vacuo to yieldthe title compound (152 mg) as a white solid.

(±)-(1S,2S,3S)-3-Amino-1-chloro-1,2,3,4-tetrahydro-2-phenanthrenol,hydrochloride

A suspension of α,α-diethoxymethyl-β-tert-butoxycarbonylamino-1-naphthalenepropanol (252mg), isomer B w as stirred in 37% aqueous hydrochloric acid at 0° C. for50 minutes. The resulting suspension was then stirred at 100° C. for 3minutes. The reaction flask was cooled at 0° C. and the precipitate wasfiltered, washed with water and dried in vacuo. The title compound (156mg) was obtained as a white solid.

Step F:

3-Amino-1-chloro-1,2,3,4-tetrahydro-2-phenanthrenol (103 mg) intrifluoroacetic acid (10 ml) was refluxed for 3 hours. The green mixturewas evaporated and the residue was taken up in methanol and acidifiedwith a solution of hydrochloric acid in diethyl ether. The evaporationresidue was treated with charcoal in methanol. Filtration gave a clearsolution which was evaporated to yield the crude compound as a solid (99mg). Recrystallization from ethanol/diethyl ether afforded the titlecompound (40 mg) as a white solid, m.p. 247° C. (dec.).

EXAMPLE 6

(±)-3-Amino-7-hexyl-3,4-dihydro-2(1H)-naphthalenone, hydrochloride

Step A:

1-(2-Nitroethenyl)-4-hexylbenzene

The title compound was prepared according to the procedure described inExample 3 step A. Starting from 4-hexylbenzaldehyde (12 g) a crudeproduct was obtained as a brown solid. Recrystallization from aceticacid yielded the title compound (9.34 g ) as a greenish solid.

Step B:

1-(2-Nitroethyl)-4-hexylbenzene

The title compound was prepared according to the procedure described inExample 3 step B. The reduction of 1-(2-nitroethenyl)-4-hexylbenzenewith sodium borohydride gave an oil as the crude product; this oil wasdistilled at 180° C. under high vacuum (0.05 mBar) to afford the titlecompound as a brown liquid (5.93 g).

Step C:

α,α-Diethoxymethyl-62-nitro-4-hexylbenzenepropanol

A mixture of 1-(2-nitroethyl)-4-hexylbenzene (5.86 g) glyoxalmonodiethylacetal (1.64 g) and potassium carbonate (178 mg) was stirredunder argon at 50° C. for 21/4hours. The mixture was diluted withdiethyl ether (60 ml ) and water was added (60 ml). The organic layerwas separated and the aqueous layer was re-extracted with diethyl ether(3×30 ml). The combined organic layers were washed with saturatedaqueous sodium chloride (100 ml) and dried over magnesium sulfate.Evaporation of solvent gave a residue which was purified bychromatograph [silica gel 35 0 g, elution with ethyl acetate:cyclohexane, 1:9 (2 1) and 2:8 (2 1)]. The title compound was obtainedas a yellow oil (3.42 g).

Step D:

α, α-Diethoxymethyl-β-tert-butoxycarbonylamino-4-hexylbenzenepropanol

A mixture of α, α-diethoxymethyl-β-nitro-4-hexylbenzenepropanol (2.31 g)and Raney nickel (0.6 g) in isopropanol (70 ml) was stirred underhydrogen at atmospheric pressure until the hydrogen absorption wascomplete. The mixture was degased in vacuo for 15 minutes and filteredthrough celite. Evaporation of solvent gave α,α-diethoxymethyl-β-amino-4-hexylbenzenepropanol (1.82 g) as an oil. Thisoil was reacted with di-tert-butyl-dicarbonate (1.19 g) in methanol (40ml). The mixture was stirred at room temperature for 2 hours. Thesolvent was evaporated and the residue was purified by chromatography[silica gel 290 g, elution with ethyl acetate: cyclohexane, 2:8 (2 1)].Two isomers of the title compound were isolated. Isomer A (0.90 g) andisomer B (0.90 g) were obtained as oils, Rf isomer A=0.30, Rf isomerB=0.19 (silica gel, ethyl acetate: cyclohexane, 1:4)

Step E:

3-Amino-7-hexyl-3,4-dihydro-2(1H)-naphthalenone, hydrochloride

A solution ofα,α-diethoxymethyl-β-tert-butoxycarbonylamino-4-hexylbenzenepropanol(170 mg) in trifluoroacetic acid (100 ml) was refluxed for 2 hours. Themixture was evaporated under reduced pressure, the residue was taken upin methanol and filtered. Evaporation gave a brown oil which was reactedagain in refluxing trifluoroacetic acid (100 ml) for 1 hours. Themixture was evaporated. The residue dissolved in methanol was acidifiedwith a solution of hydrochloric acid in diethyl ether and the mixturewas evaporated. The acidification process was repeated twice. Theresidue was dried in vacuo to yield a brown solid (56 mg).

EXAMPLE 7 3-Amino-3,4-dihydro-6,8-dimethoxy-2(1H)-naphthalenone,hydrochloride

Step A:

1-(2-Nitroethenyl)-3,5-dimethoxybenzene

A mixture consisting of 3,5-dimethoxybenzaldehyde (20 g), nitromethane(20 ml), ammonium acetate (8 g) and acetic acid (80 ml) was refluxtedfor 11/2 hours and the reaction mixture was poured into ice-water. Theyellow solid which separated was filtered and dried under high vacuum toyield the title compound (22.3 g).

Step B:

1-(2-Nitroethyl)-3,5-dimethoxybenzene

To a well stirred suspension of sodium borohydride (5 g) in a mixture ofdioxane (100 ml) and absolute ethanol (30 ml) was added dropwise asolution of 1-(2-nitroethenyl)-3,5-dimethoxybenzene (12.6 g) in dioxane(100 ml) over a 1 hour period. Following addition the mixture wasstirred for an additionnal 45 minutes period. To the resultingsuspension were added ice-water (120 ml) and 50% aqueous acetic acid (10ml). Agitation was maintained for 1 hour and the clear solution wasconcentrated under reduced pressure. The residue was extracted withethyl acetate/water, the organic layer was washed with saturated aqueoussodium chloride and dried over magnesium sulfate. Evaporation ofsolvents afforded the crude title compound (10.8 g). Trap to trapdistillation under high vacuum (0.05 Millibars) at 180° C. yielded1-(2-nitroethyl)-3,5-dimethoxybenzene as a colorless oil (6.8 g).

Step C:

α, α-Diethoxymethyl-β-nitro-3,5-dimethoxybenzenepropanol

A mixture of 1-(2-nitroethyl)-3,5-dimethoxybenzene (6.68 mg), of glyoxalmonodiethyl acetal (2.07 g) and of potassium carbonate (0.216 g) wasstirred at 50° C. for 4 hours. The reaction mixture was diluted withdiethyl ether, washed with water (2×50 ml) and saturated aqueous sodiumchloride (50 ml). After drying over magnesium sulfate the organicsolution was evaporated under reduced pressure to afford a residue whichwas purified on silica gel [180 g, elution with ethylacetate:cyclohexane, 1:9 (1 1), 1:4 (1 1)]. After evaporation ofsolvents the title compound was obtained as an oil (2.41 g).

Step D:

α,α-Diethoxymethyl-β-amino-3,5-dimethoxybenzenepropanol

α,α-Diethoxymethyl-β-nitro-3,5-dimethoxybenzenepropanol (3.39 g) washydrogenated in isoproipanol (50 ml) over Raney nickel at atmosphericpressure and room temperature. When hydrogen absorption was complete,the reaction mixture was degased for 15 minutes under vacuum and thecatalyst was filtered on celite. The solvent was evaporated under vacuumto yield the title compound as an oil (2.38 g).

Step E:

α, α-Diethoxymethyl-β-tert-butoxycarbonylamino-3,5-dimethoxybenzenepropanol

α,α-diethoxymethyl-β-amino-3,5-dimethoxybenzenepropanol (2.38 g) wasreacted with di-tert-butyl-dicarbonate (1.82 g) in methanol (30 ml) for1 hour at room temperature. The solvent was evaporated under vacuum andthe residue was purified by chromatography on silica gel [130 g, elutionwith ethyl acetate:cyclohexane, 1:9-0.7 1), 1:4 (1 1) and 3:7(1 1)]. Twoisomers of the title compound were isolated, isomer A as an oil (0.98 g)and isomer B (0.53 g) that could be crystallized from pentane, m.p.73.5°-75° C. R_(F) isomer A=0.33, R_(F) isomer B=0.20 (silica gel, ethylacetate: cyclohexane, 3:7).

Step F:

3-amino-3,4-dihydro-6,8-dimethoxy-2(1H)-naphtalenone, hydrochloride

α,α-Diethoxymethyl-β-tert-butyoxycarbonylamino-2,5-dimethoxy-benzenepropanol(200 g) was dissolved in aqueous 37% hydrochloric acid (20 ml) cooled at0° C. The resulting red solution was warmed at 100° C. for 3 minutes andthen immediately cooled at 0° C. Evaporation of the reaction mixtureyielded a brown solid which was recrystallized from an ethylacetate/methanol mixture to give the title compound as a brown solid(101 mg).

EXAMPLE 8 3-Amino-1-fluoro-3,4-dihydro-2(1H)-naphthalenone hydrochloride(cis-chlorohydrin approach)

Step A:

β-Nitro-α,α-(diethoxymethyl)benzenepropanol

Under argon a mixture of 1-nitro-2-phenylethane (18.11 g), glyoxalmonodiethylacetal (12.23 g) and potassium carbonate (1.26 g) was stirredat 50°-55° C. for 6 hours. The mixture was then diluted with diethylether, washed with water and saturated aqueous sodium chloride and driedover magnesium sulfate. The solvent was removed at reduced pressure andthe crude material was purified on silica gel (500 g, elution with ethylacetate: cyclohexane, 15:85) to give the title compound (22.08 g ) as ayellow oil.

Step B:

β-Tert-butoxycarbonylamino-α,α-(diethoxymethyl)benzenepropanol

β-Nitro-α,α-(diethoxymethyl)benzenepropanol (14.7 g) and Raney nickel in2-propanol (300 ml) were stirred at room temperature under hydrogen atatmospheric pressure. When hydrogen absorption was complete the mixturewas degased in vacuo for 15 minutes and filtered through celite using2-propanol. The solvent was evaporated in vacuo to yieldβ-amino-α,α-(diethoxymethyl)benzenepropanol (12.88 g) as an oil.

Di-tert-butyl-dicarbonate (12 g) was added to a solution ofβ-amino-α,α-(diethoxymethyl)benzenepropanol (12.88 g) in methanol (100ml). The mixture was stirred for 5 hours at room temperature and thesolvent was evaporated in vacuo. The residue was chromatographed [silicagel, 1 kg, elution with cyclohexane:ethyl acetate mixtures, 95:5 (1 1),9:1 (2 1), 8:2 (2 1) and 7:3 (6 1)]. Two isomers of the title compoundwere isolated as oils, isomer A (6.41 g) and isomer B (4.30 g), Rfisomer A=0.26, Rf isomer B=0.21 (silica gel, ethyl acetate: hexane,1:3).

Step C:

(±)-(1R, 2S,3R)-3-Amino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol,hydrochloride (amino-cis-chlorohydrin)

β-Tert-butoxycarbonylamino-α,α-(diethoxymethyl)benzenepropanol, isomer A(4.213 g) was stirred in 37% aqueous hydrochloric acid (40 ml) at 0° C.for 45 minutes and at 100° C. for 3 minutes. The mixture was cooled inan ice bath. The precipitate was filtered, washed with water and driedin vacuo to afford the title compound (1.477 g) as a white solid, m.p.189° C. (dec.)

Step D:

(±)-(1R,2S,3R)-3-Tert-butoxycarbonylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol(BOC-amino-cis-chlorohydrin)

To a well stirred mixture of di-tert-butyl-dicarbonate (720 mg) and(±)-(1R,2S,3R)-3-amino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenolhydrochloride (710 mg) in methanol (15 ml) was added dropwise a solutionof triethylamine (390 mg) in methanol (10 ml). Stirring was maintainedfor 3 hours at room temperature and the mixture was evaporated underreduced pressure. The residue was taken up into methylene chloride, theorganic solution was washed with water, saturated aqueous sodiumchloride and dried over magnesium sulfate. Evaporation of solventafforded a residue which was recrystallized from an hexane/diethyl ethermixture to yield the title compound (340 mg) as a white solid.

Step E:

(±)-(1S,2S,3R)-3-Tert-butoxycarbonylamino-1-fluoro-1,2,3,4-tetrahydro-2-naphthalenol

A mixture of (35)-(1R,2S,3R)-3-tert-butoxycarbonylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol(196 mg) and AMBERLYST A-26F resin (1.04 g) in hexane (10 ml) wasrefluxed for 4 hours. The resin was filtered and washed with warmhexane. The filtrate was evaporated in vacuo and the residue waschromatographed (silica gel 20g, elution with cyclohexane:ethyl acetate,4:1) to afford the title compound (24 mg) as an oil.

Step F:

3-Tert-butoxycarbonylamino-1-fluoro-3,4-dihydro-2(1H)-naphthalenone

To a solution of(±)-(1S,2S,3R)-3-tert-butoxycarbonylamino-1-fluoro-1,2,3,4-tetrahydro-2-naphthalenol(140 mg) in anhydrous methylene chloride (5 ml) was added Dess-Martinperiodinane (340 mg) and tert-butyl-alcohol (70 mg). Stirring wasmaintained at room temperature for 31/2 hours. The reaction was quenchedwith isopropanol and the reaction mixture was poured on a silica gelcolumn (50 g, elution with cyclohexane: ethyl acetate, 9:1) to affordthe title compound (105 mg) as an oil.

Step G:

3-Amino-1-fluoro-3,4-dihydro-2(1H)-naphthalenone, hydrochloride

Under argon3-tert-butoxycarbonylamino-1-fluoro-3,4-dihydro-2(1H)-naphthalenone (105mg) was treated with a saturated solution of hydrochloric acid indiethyl ether for 21/2 hours. The solid which precipitated out wasfiltered and dried in vacuo to yield the title compound as a white solid(65 mg).

EXAMPLE 9 3-Amino-1-fluoro-3,4-dihydro-2(1H)-naphthalenone,hydrochloride (trans-chlorohydrin approach)

Step A:

(±)-(1R,2R,3R)-3-Amino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol,hydrochloride (amino-trans-chlorohydrin)

β-Tert-butoxycarbonylamino-α,α-(diethoxymethyl)benzenepropanol isomerB(4.3 g) was treated as in Example 8 step C to yield the title compound(1.53 g) as a white solid, m.p. 198° C. (dec.).

Step B:

(±)-(1R,2R,3R)-3-Tert-butoxycarbonylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol(BOC-amino-trans-chlorohydrin)

To a well stirred mixture of (±)-(1R,2R,3R)-3-amino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride(1g) and di-tert-butyl-dicarbonate (1g) in methanol (20 ml) was addeddropwise a solution of triethylamine (0.43 g) in methanol (20 ml) over aperiod of 40 minutes. The mixture was stirred overnight at roomtemperature and evaporated in vacuo. The residue was crystallized from ahexane/diethyl ether mixture to give the title compound as a whitesolid.

Step C:

(±)-(1S,2R,3R)-3-Tert-butoxycarbonylamino-1,3-epoxy-1,2,3,4-tetrahydro-naphthalene

A solution of(±)-(1R,2R,3R)-3-tert-butoxycarbonylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol(348 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (400 mg) intetrahydrofuran (10 ml) was refluxed for 11/2 hours. The mixture wasdiluted with methylene chloride, washed with saturated aqueous sodiumchloride, dried over magnesium sulfate and concentrated in vacuo. Theresidue was recrystallized from cyclohexane (193 mg) to yield the titlecompound as a white solid, m.p. 118°-119° C.

Step D:

(±)-(1R,2R,3R)-3-Tert-butoxycarbonylamino-1-fluoro-1,2,3,4-tetrahydro-2-naphthalenol

To a solution of(±)-(1S,2R,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-1,2,3,4-tetrahydro-naphthalene(100 mg) in anhydrous diethyl ether (6 ml) cooled in an ice-bath wasadded 70% hydrogen fluoride-pyridine (0.24 ml). The mixture was stirredat 0° C. for 9 hours, ice was added and the reaction mixture wasneutralized by addition of solid sodium bicarbonate (1.2 g) at 0° C. andextracted with diethyl ether. The organic layer was dried over magnesiumsulfate and evaporated to afford the crude title compound as an oil (65mg). This crude material was purified by chromatography on silica gel(10 g, elution with ethyl acetate:cyclohexane, 2:8) and the resultingmaterial (35 mg) was crystallized from a diethyl ether/pentane mixtureto afford the title compound as a white solid, m.p. 98°-99° C.

Step E:

3-Tert-butoxycarbonylamino-1-fluoro-3.4-dihydro2(1H)naphthalenone

As in Example 8, Step F.

Step F:

3-Amino-1-fluoro-3,4-dihydro-2(1H)-naphthalenone, hydrochloride

As in Example 8, Step G.

EXAMPLE 10 1-Isoamylamino-3amino-3,4-dihydro-2(1H)-naphthalenone,dihydrochloride

STEP A:

(±)-(1S,2R,3R)-1-Isoamylamino-3-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-2-naphthalenol

Under argon a solution of(1R,2S,3R)-3-tert-butoxycarbonylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol(BOC-amino-cis-chlorohydrin) (500 mg) in anhydrous tetrahydrofuran wasrefluxed with isoamylamine (1.0 ml) and triethylamine (250 μl) for 5hours at 90° C. The mixture was poured in aqueous 5% sodium bicarbonateand extracted with methylene chloride. The organic solution was driedover magnesium sulfate and evaporated under vacuum to yield an oil.Crystallization of this oil in hexane yielded the title compound as awhite solid (270 mg).

Step B:

(±) (1S,2S,3R)-N¹, N³ -Bis(tert-butoxycarbonyl)-N¹-isoamyl-1,3-diamino-1,2,3,4-tetrahydro-2-naphthalenol

(±)-(1S,2R,3R)-1-isoamylamino-3-tert-butoxycarbonyl-amino-1,2,3,4-tetrahydro-2-naphthalenol (200 mg) was treated withdi-tert-butyl-dicarbonate (170 mg) in methanol (5 ml) for 24 hours atroom temperature. Evaporation of the reaction mixture under vacuum gavean oil which was filtered through silica gel (elution withcyclohexane:ethyl acetate, 4:1) to yield the title compound as an oil(150 mg).

Step C:

N¹ N³ -Bis(tert-butoxycarbonyl)-N¹-isoamyl-1,3-diamino-3,3-dihydro-2(1H)-naphthalenone

Under argon to a solution of (±)-(1S,2S,3R)-N¹ N³-bis-(tert-butoxycarbonyl)-N¹ -isoamyl-1,3-diamino1,2,3,4-tetrahydro-2-naphthalenol (140 mg) in anhydrous methylenechloride (5 ml) was added Dess-Martin periodinane (230 mg) at roomtemperature. After 1 hour stirring at room temperature the reactionmixture was filtered through silica gel (elution with cyclohexane:ethylacetate, 9:1) to yield the title compound as an oil (100 mg).

Step D:

1-Isoamylamino-3-amino-3,4-dihydro-2(1H)-naphthalenone, dihydrochloride

Under argon N¹ N³ -bis(tert-butoxycarbonyl)-N¹ -isoamyl-1,3-diamino-3,4-dihydro-2(1H)-naphthalenone (90 mg) was dissolved into asaturated solution of hydrochloric acid in diethyl ether. The mixturewas stirred for 6hours at room temperature. The precipitate was decantedfrom the etheral solution and dried under vacuum. The title compound wasobtained as a white solid (50 mg).

EXAMPLE 11 3-Amino-3,4-dihydro-1-isopropyloxy-2(1H)-naphthalenone,hydrochloride

Step A:

(±)-(1R,2R,3R)-3-Tert-butoxycarbonylamino-1,2,3,4-tetrahydro-1-isopropyloxy-2-naphthalenol

Under argon to a solution of(±)-(1S,2R,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-1,2,3,4-tetrahydro-naphthalene(96 mg) in methanol (4 ml) was added titanium isopropoxyde (0.19 ml).The mixture was warmed for 14 hours in an oil bath maintained at 96° C.Evaporation of the warm mixture under an argon flow gave a residue whichwas purified on a silica gel column (22 g, elution with ethylacetate:cyclohexane, 1:4). After evaporation of solvents was recoveredan oil which was crystallized from a pentane/diethyl ether mixture toafford the title compound as a white solid (56 mg).

Step B:

3-Tert-butoxycarbonylamino-3,4-dihydro-1-isopropyloxy-2-(1H)-naphthalenone

Under argon to a solution of (±)-(1R,2R,3R)-3-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-1-isopropyloxy-2-naphthalenol (50mg) in anhydrous methylene chloride (4 ml) was added Dess-Martinperiodinane (100 mg). Agitation was maintained at room temperature for 2hours. The reaction mixture was filtered on a silica gel column (10 g,elution with ethyl acetate:cyclohexane. 1:9) to afford the titlecompound as an oil (38 mg).

Step C:

3-Amino-3,4-dihydro-1-isopropyloxy-2(1H)naphthalenone, hydrochloride

Under argon 3-tert-butoxycarbonylamino-3,4-dihydro-1-isopropyloxy-2(1H)-naphthalenone (30 mg) was dissolved in formic acid (1ml) and the mixture was set aside at room temperature for 4 hours.Formic acid was evaporated under vacuum and the residue was acidifiedwith aqueous 0.01N hydrochloric acid. Evaporation of the mixture andrecrystallization of the residue in an ethyl acetate/methanol mixtureyielded the title compound as a white solid (20 mg).

EXAMPLE 12

3-Amino-3,4 -dihydro-1-methyl-2(1H)-naphthalenone, hydrochloride

Step A:

(±)-1R,2S,3R)-3 Tert-butoxycarbonylamino-1,2,3,4-tetrahydro-1-methyl-2-naphthalenol

Under argon to a solution of(±)-(1S,2R,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-1,2,3,4-tetrahydro-naphthalene(108 mg) in hexane (10 ml) was added a 2 M solution of trimethylaluminumin hexane (0.30 ml), the mixture was heated under reflux for 31/2 hoursand was quenched by addition of a 2 M aqueous solution of ammoniumchloride adjusted to pH 8 with ammonium hydroxide. The resultingsuspension was extracted with ethyl acetate. The ethyl acetate solutionwas dried over magnesium sulfate and evaporated under vacuum to give acolorless oil which was purified by preparative thin layerchromatography on silica gel (elution with ethyl acetate:cyclohexane,3:8) to afford the title compound as a solid (32 g).

Step B:

3-Tert-butoxycarbonylamino-3,4-dihydro-1-methyl-2-(1H)naphthalenone

The oxidation of(±)-(1R,2S,3R)-3-tert-butoxycarbonyl-amino-1,2,3,4-tetrahydro-1-methyl-2-naphthalenolwas performed as in Example 11, Step B.

Step C:

3-Amino-3,4-dihydro-1-methyl-2(1H)-naphthalenone, hydrochloride

The BOC deprotection was achieved in a solution of hydrochloric acid indiethyl ether as described in Example 8, Step G.

EXAMPLE 133-Amino-1,1-difluoro-3,4-dihydro-3,4-dihydro-2(1H)-naphthalenonehydrochloride

Step A:

(±)-(1R,2S,3R)-3-Benzoylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol

To a mixture of(±)-(1R,2S,3R)-3-amino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol (547mg) in water (10 ml) and benzoylchloride (367 mg) in toluene (6 ml) wasadded dropwise a solution of sodium bicarbonate (420 mg) in water (10ml) over a period of 30 minutes. Stirring was maintained at roomtemperature for an additional period of 30 minutes. The mixture wasextracted with chloroform, washed with saturated aqueous sodium chlorideand evaporated in vacuo. Recrystallization of the residue from acyclohexane/ethyl acetate mixture yielded the title compound (357 mg) asa white solid.

Step B: (±)-(3aR,9R,9aR)-9-Chloro-3a,4,9,9a-tetrahydro-2-phenylnaphth[2,3-d]oxazole

(±)-(1R,2S,3R)-3-Benzoylamino-1-chloro-1,2,3,4-tetrahydro-2-naphthalenol(204 mg) in thionyl chloride as solvent was stirred at 50° C. for 2hours. Evaporation of thionyl chloride gave a solid residue which wastriturated in warm ethyl acetate and filtered to yield the titlecompound (151 mg) as a white solid.

Step C:

(±)-(3aR,9aR)-3a,4,9,9a-Tetrahydro-2-phenyl-naphth[2,3-d]oxazol-9-ol

To a solution of (±)-(3aR,9R, 9aR)-9-chloro-3a,4,9,9a-tetrahydro-2-phenyl-naphth[2,3-d]oxazole (360 mg) in2-methoxyethanol (10 ml) was added a solution of lithium hydroxydemonohydrate (67 mg) in water (2 ml). The mixture was warmed at 90° C.for 1/2 hour and the title compound was precipitated by addition ofwater. Filtration, washing with water and drying in vacuo gave the titlecompound as a yellow solid (205 mg).

Step D:

(±)-(3aR,9aR)-3a,4-Dihydro-2-phenyl-naphth-[2,3-d]-oxazol-9(9aH)-one

Under argon to a solution of (±)-(3aR,9aR)-3a, 4,9,9a-tetrahydro2-phenyl-naphth-[2,3-d]oxazol-9-ol in methylene chloride (10 ml) wasadded Dess Martin periodinane (640 mg) and tert-butylalcohol (56 mg).After 5 hours stirring at room temperature, isopropanol was added andthe reaction mixture was filtered on a silica gel column (elution withcyclohexane: ethyl acetate, 40:1). Evaporation of solvents gave thetitle compound as an oil (150 mg).

Step E:

(±)-(3aR,9aR)-9,9-Difluoro-3a, 4,9,9a-tetrahydro-2-phenylnaphth[2,3-d]oxazole

To a solution of(±)-(3aR,9aR)-3a,4-dihydro-2-phenylnaphth[2,3-d]oxazol-9(9aH)-one (100mg) in methylene chloride (10 ml) was added diethylaminosulfurtrifluoride (100 μl). The mixture was stirred for 24 hours at roomtemperature and poured into ice-water. The organic layer was washed withsaturated aqueous sodium chloride and dried over magnesium sulfate. Thesolvent was evaporated in vacuo and the residue was crystallized in acyclohexane/ethyl acetate mixture to yield the title compound 55 mg).

Step F:

(±)-(2R,3R)-3-Amino-1,1-difluoro-1,2,3,4-tetrahydro-2-naphthalenol,hydrochloride

A suspension of(±)-(3aR,9aR)-9.9-difluoro-3a,4,9,9a-tetrahydro-2-phenyl-naphth[2,3d]oxazole (50 mg) in 2.5 N aqueous hydrochloric acid was refluxedovernight. The mixture was concentrated in vacuo and the residue wascrystallized from water. Benzoic acid was filtered and the filtrate wasconcentrated to afford the crude product which was recrystallized frommethanol/ethyl acetate affording the title compound (35 mg).

Step G:

(±)-(2R,3R)-3-Tert-butoxycarbonylamino-1,1-difluoro-1,2,3,4-tetrahydro-2-naphthalenol

A mixture of(±)-(2R,3R)-3-amino-1,1-difluoro-1,2,3,4-tetrahydro-2-naphthalenolhydrochloride (50 mg), di-tert-butyl-dicarbonate (50 mg) andtriethylamine (25 mg) in methanol (2 ml) was stirred at room temperaturefor 4 hours. The mixture was concentrated in vacuo and the residue wascrystallized from a cyclohexane/ethyl acetate mixture to yield the titlecompound (45 mg).

Step H:

3-Tert-butoxycarbonylamino-1,1-difluoro-3,4-dihydro-2(1H)-naphthalenone

3-Tert-butoxycarbonylamino-1,1-difluoro-1,2,3,4-tetrahydro-2-naphthalenolwas oxidized to the title compound by the procedure described in Example8, Step F.

Step I:

3-Amino-1,,1-difluoro-3,4-dihydro-2(1H)-naphthalenone, hydrochloride

Deprotection of(±)-3-tert-butoxycarbonylamino-1,1-difluoro-3,4-dihydro-2(1H)-naphthalenonewas achieved using the procedure described in Example 8, Step G to yieldthe title compound.

EXAMPLE 14 3-Amino-octahydro-2-(1H) naphthalenone, hydrochloride

Step A:

3-Tert-butoxycarbonylamino-decahydro-2-naphthalenol

A solution of3-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-2-naphthalenol (1.05 g) inacetic acid (100 ml) was hydrogenated over platinum oxyde (121 mg) underpressure (5.5.6 bars) at room temperature for 3 days. The catalyst wasfiltered and the solvent was evaporated under vacuum. The residue waspurified by chromatography on silica gel [140 g, elution with ethylacetate:cyclohexane, 2:8 (0.7 1) and 5:7 (1 1)] to afford the titlecompound as an oil (915 mg).

Step B:

3-Tert-butoxycarbonylamino-octahydro-2(1H)-naphthalenone

Under argon to a solution of 3-tertbutoxycarbonylaminodecahydro-2-naphthalenol (0.27 g) in methylenechloride (5 ml was added pyridinium dichromate (572 mg), molecularsieves 3A powder (791 mg) and acetic acid (100 μl ). The reactionmixture was stirred for 50 minutes at room temperature. The blackmixture was filtered through a silica gel column (60 g, elution withethyl acetate:cyclohexane, 1:4) to give, after evaporation of solvents,the title compound as a viscous oil (165 mg).

Step C:

3-Amino-octahydro-2(1H)-naphthalenone, hydrochloride

Under argon 3-tert-butoxycarbonylamino-decahydro-2-naphthalenone (165mg) was treated with a saturated solution of hydrochloric acid indiethyl ether (10 ml). The mixture was left aside for 24 hours, aprecipitate was formed. The supernatant was discarded and the solidwashed with anhydrous diethyl ether to yield the title compound as ayellow solid (90 mg). It was recrystallized from a cyclohexane/ethylacetate/methanol mixture to afford the title compound as a white solid.

The compounds of Formula I, and the pharmaceutically acceptable saltsthereof, can be administered to a mammalian specie (e.g., humans) as ananalgesic agent due to their ability to inhibit an enkephalin-degradingaminopeptidase.

It is well known that the weak and shortlasting analgesic activity ofendogenous enkephalins can be attributed to their rapid inactivation.Enkephalins are metabolized by several hydrolytic enzymes present in thebrain: (1) aminopeptidases release the Tyr¹ residue, (2) a dipeptidylaminopeptidase releases the Tyr¹ -Gly² residue and (3) two enzymescleave the penultimate Gly³ -Phe⁴ bond to release an intact dipeptidefragment, angiotensin-converting enzyme, and a discrete enzyme commonlydesignated enkephalinase.

It has been suggested that both enkephalinase and an aminopeptidaseactivity (probably membrane bound) play key roles in enkephalinmetabolism. The compounds of this invention inhibit the aminopeptidaseactivity and thus act as analgesic agents.

In addition to their use as analgesic agents, the compounds of thisinvention (I) are also useful as agents which may be used in conjunctionwith known therapeutic agents. For example, aminopeptidase inhibitors(such as bestatin) are known to exert an immunomodulating effect andtherefore have been found to be useful in the conjunctive therapy withagents useful in the treatment of such diseases as cancer and acquiredimmuno deficiency syndrom. Indeed, compounds of this invention have beenfound to potentiate the effect of natural killer cells.

Using standard in vitro and in vivo assays designed to demonstrateaminopeptidase inhibiting properties and end-use applications(respectively) as well as by comparative tests with aminopeptidaseinhibitors known to have been useful in exerting beneficial end-useapplications, the compounds of this invention exert their beneficialeffects at a daily dose of about 0.1 mg to about 25 mg of compound perkilogram of body weight.

A compound of Formula I, or a pharmaceutically acceptable salt thereof,can be administered to patients orally or parenterally in an effectiveamount within the daily dosage range of about 0.1 to about 25 mg ofcompound per kilogram of patient body weight. Administration ispreferably in 2 to 4 divided doses and compounds may be administeredenterally or parenterally in accordance with the condition of thepatient being treated using pharmaceutical formulations according totechniques well known in the art.

As is true for most generic classes of compounds which are suitable foruse as chemotherapeutic use, certain subgeneric groups and certainspecific compounds are preferred. In this instance, those compounds ofFormula I wherein the dotted lines represent a facultative double bondare preferred over their saturated analogs, compounds wherein R₁ is Hand R₂ is H, F, Cl are most preferred with alkyl, alkoxy, alkylamino,acyloxy or acylamino being other preferred R₂ moieties when R₁ is H, andwhen R₁ is other than H, then it is preferred that both R₁ and R₂ befluoro, chloro or alkyl. When R₆, R₇ and R₉ are H, it is preferred thatR₈ be H, alkyl, alkoxy, alkylamino or alkylthio. When any of the R₇ andR₈, R₈ and R₉, or R₆ and R₇ combinations together with the carbon atomsto which they are attached, form a benzene ring then it is preferredthat R₆ and R₉, R₆ and R.sub. 7,and R₈ and R₉, respectively, be H.Preferred compounds of this type are the R₁ and R₂ substituted orunsubstituted 3-amino-3,4-dihydro-2(1H)phenanthrenones and the2-amino-1,2-dihydro-3(4H)phenanthrenones. When the dotted lines of thecompounds of Formula I represent a saturated ring (thereby forming thedecalin analogs of the unsaturated compounds) it is preferred that allthe R₆ to R₉ substituents be hydrogen or that one be alkyl. When R₁ andR₂ are H and substituents are present on the benzenoid moiety, it ispreferred that such substituents be 7,9-dimethoxy, 7,9-dichloro, or7,9-dihydroxy. Preferred specific compounds are those wherein R₁ and R₂are H,H, or F,F, Cl,Cl, or H,F, or H,Cl whilst R₆, R₇, R₈ and R₉ are H,or R₈ is hexyl, or R₇ and R₉ are dimethoxy, or dichloro, or dihydroxy,or R₆ and R₇, together with the carbon atoms to which they are attached,form a 3-amino-3,4-dihydro-2(1H)phenanthrenone, or when R₈ and R₉,together with the carbon atoms to which they are attached, form a2-amino- 1,2-dihydro-3(4H)phenanthrenone. Other preferred compounds arethose wherein R₂ is methyl, isopropoxy or isoamylamino whilst R₁, R₆ R₇,R₈ and R₉ are H. Of course, the foregoing specific compounds arecompounds wherein the dotted lines of Formula I represent double bonds.

We claim:
 1. A compound of the formula: ##STR10## the enantiomeric formsand mixture thereof, and the pharmaceutically acceptable salts thereofwherein the dotted lines represent facultative double bonds, R₁ is H, F,Cl, C₁₋₆ alkyl, OH or c₁₋₆ alkoxy, R₂ is H, Cl, F or C₁₋₆ alkyl, each ofR₆, R₇, R₈ and R₉ is H, Cl, F or C₁₋₆ alkyl, and when R₆ and R₇, R₇ andR₈, and R₈ and R₉ are taken together with the carbon atoms to which theyare attached, they form a 6-membered carboxyclic moiety with the provisothat when the depicted ring moiety having the facultative double bondsis saturated R₁, R₂, R₆, R₇, R₈, and R₉ cannot all be hydrogen, and withthe further proviso that when the depicted ring moiety having thefacultative double bonds is saturated then the 6-membered carbocyclicmoiety formed is also saturated.
 2. Compounds of claim 1 wherein thedotted lines represent double bonds.
 3. Compounds of claim 1 wherein R₁and R₂ are hydrogen.
 4. Compounds of claim 2 wherein R₁ and R₂ arehydrogen.
 5. Compounds of claim 2 wherein R₁ is H and R₂ is fluoro. 6.Compounds of claim 2 wherein R₁ is H and R₂ is chloro.
 7. Compounds ofclaim 2 wherein R₁ and R₂ are fluoro.
 8. Compounds of claim 2 wherein R₁is F and R₂ is Cl.
 9. Compounds of claim 3 wherein R₆, R₇, R₈ and R₉ areH.
 10. Compounds of claim 2 wherein R₆ and R₇,together with the carbonatoms to which they are attached, form a3-amino-3,4-dihydro-2(1H)phenanthrenone.
 11. Compounds of claim 2wherein R₈ and R₉, together with the carbon atoms to which they areattached, form a 2-amino-1,2-dihydro-3(4H)phenanthrenone.
 12. A compoundof claim 4 wherein R₆, R₇, R₈ and R₉ are H.
 13. A compound of claim 4where R₈ is hexyl and R₆, R₇ and R₉ are H.
 14. A compound of claim 10wherein R₁ and R₂ are H.
 15. A compound of claim 11 wherein R₁ and R₂are H.